Introduction

Thalassaemia is a genetic and diverse group of diseases characterised by a reduced production of either alpha or beta chains of haemoglobin (Hb). Haemoglobin is the molecule responsible for transporting oxygen within red blood cells (RBCs). It is composed of two types of proteins, alpha and beta. When the body fails to produce adequate amounts of one or both of these proteins, the formation of red blood cells is impaired, leading to insufficient oxygen transport, which results in anaemia that typically occurs in early childhood and persists throughout an individual's life. Thalassaemia is a hereditary condition, indicating that at least one parent must be a carrier of the disorder. This condition arises either through genetic mutation or deletion of specific gene segments.¹

Alpha Thalassaemia

Alpha thalassaemia occurs due to the deletion of the alpha gene, leading to decreased or complete absence of alpha-globin chain production. The alpha-globin gene consists of four alleles, and the severity of the disease varies from mild to severe depending on the number of alleles deleted. Deletion of all four alleles represents the most serious form, resulting in the complete absence of alpha-globin production. In this scenario, the surplus gamma chains, which are typically present during foetal development, combine to form tetramers. This condition is incompatible with life and leads to hydrops fetalis. Deletion of one allele represents the least severe form and is typically asymptomatic in clinical settings.¹

Beta Thalassaemia

Specific changes in the beta-globin gene cause beta thalassaemia. It is classified into three groups based on the characteristics of the mutation in the beta-globin gene.

Beta-Plus Thalassaemia

This is a heterozygous mutation that leads to thalassaemia minor, characterised by insufficient production of beta chains. It is usually mild and often does not present with any symptoms.

Beta-Zero Thalassaemia

This is a homozygous mutation in the beta-globin gene that leads to thalassaemia major, resulting in the complete absence of beta chains. Clinical features include:

• Yellowing of the skin and eyes
• Slowed growth
• Enlargement of the liver and spleen
• Hormonal issues
• Severe anaemia requiring lifelong blood transfusions

Beta Thalassaemia Intermedia

This condition falls between the above two types and is characterised by mild to moderate clinical symptoms.

• A single altered gene results in mild indications and effects. This condition is referred to as thalassaemia minor
• Two altered genes result in moderate to severe indications and effects. This condition is known as thalassaemia major, or Cooley anaemia

People with beta thalassaemia major require regular blood transfusions. A blood transfusion is a routine procedure in which donated blood is administered to restore functional and healthy haemoglobin levels in the bloodstream. This treatment involves administering donated blood into the body through a small plastic tube placed intravenously into a blood vessel, and may last from one to four hours. In severe cases of beta thalassaemia major, patients may require transfusions as frequently as every two to four weeks. Patients with beta thalassaemia intermedia may also require blood transfusions in specific circumstances, such as during an illness or infection, or in preparation for surgery.²

Goals of Transfusion Therapy in Thalassaemia

The protocol for the routine administration of red blood cells to patients with thalassaemia emphasises key concepts such as setting appropriate transfusion therapy goals and ensuring the highest possible safety of transfused blood. The main objectives are:³

• Maintaining the vitality and functionality of red blood cells throughout preservation to guarantee an adequate oxygen supply
• Utilising donor red blood cells in the recipient with regular recovery and a normal half-life
• Attaining the appropriate haemoglobin levels
• Prevention of adverse consequences, such as the transmission of infectious agents

Whom to Transfuse?

The following criteria should be considered when deciding whom to transfuse:

• Confirmed diagnosis of thalassaemia
• Laboratory criteria: haemoglobin (Hb) level below 70 g/L on two occasions more than two weeks apart, excluding all other contributing factors such as infections
• Clinical criteria, regardless of haemoglobin level: any of the following with a haemoglobin level above 70 g/L:
  • Major indicators of anaemia
  • Insufficient growth or failure to thrive
  • Complications caused by increased intramedullary haematopoiesis, including facial changes and pathological fractures
  • Clinically significant extramedullary haematopoiesis⁴

Indications for Transfusion Therapy

Beta-Thalassaemia Major

Regular blood transfusions are necessary for patients with beta thalassaemia major.²

Beta-Thalassaemia Intermedia

In certain circumstances, blood transfusions may be necessary for patients with beta thalassaemia intermedia.²

Types of Transfusion Programmes

Regular (Chronic) Transfusion Regimen

The recommended care for thalassaemia major consists of ongoing, lifelong management. Regular blood transfusions are typically administered every two to five weeks to maintain the pre-transfusion haemoglobin level between 90 and 105 g/L. This transfusion plan supports proper growth and enables normal physical activity, thereby sufficiently reducing bone marrow activity in the majority of patients and minimising the accumulation of iron from transfusions.⁴

Intermittent or On-Demand Transfusions

Patients with beta thalassaemia intermedia or haemoglobin H disease may require infrequent blood transfusions. In particular, a transfusion may be necessary when the body is under physiological stress, such as during an infection, pregnancy, or surgery.⁵

Benefits of Transfusion Therapy

For patients with thalassaemia, blood transfusions are primarily performed to treat severe anaemia. Due to the lack of functional haemoglobin, the body is unable to obtain sufficient oxygen, making even basic tasks such as walking or breathing difficult. The main advantages of blood transfusion include:⁶

• Better oxygenation: donated red blood cells replace the missing haemoglobin, restoring the body's oxygen levels to normal
• Reduction of bone deformities: untreated thalassaemia may lead to skeletal abnormalities as the bone marrow attempts to produce more red blood cells. Transfusion reduces this strain on the bone marrow
• Better quality of life: transfusion can make patients feel physically better and more energetic, enabling them to focus on work, education, or other daily activities

Risks and Complications of Transfusion Therapy

Iron Overload

Iron overload is one of the potential complications in individuals with beta thalassaemia major and intermedia, arising from two main causes. First, regular blood transfusions lead to the accumulation of excess iron in the body. Second, the gastrointestinal system may absorb more dietary iron as a result of beta thalassaemia. As the body cannot eliminate excess iron, ongoing transfusion therapy results in progressive iron buildup, which affects multiple organ systems. Medications such as deferiprone (Ferriprox) and deferasirox (Exjade) are used to remove excess iron from the body.²

Transfusion Reactions

Allergic Reactions

Allergic reactions may be caused by plasma proteins and can range from mild to severe. Occasional mild allergic reactions can be managed through the administration of antihistamines or corticosteroids prior to transfusion. Repeated allergic reactions can be reduced by washing the red blood cells to remove plasma. Patients with severe allergic reactions and IgA deficiency may require blood from IgA-deficient donors.⁴

Febrile Non-Haemolytic Reactions

Febrile non-haemolytic transfusion reactions (FNHTRs) are common transfusion responses with an average per-unit incidence of 1% to 3%. The diagnosis of FNHTR is made by ruling out other potential causes of fever and by observing the patient for signs of fever and chills during or within four hours of the end of the transfusion, without any evidence of haemolysis.⁷ Previously, FNHTRs were quite frequent; however, leucoreduction has significantly reduced their occurrence.⁴

Acute Haemolytic Reactions

Symptoms of an acute haemolytic transfusion reaction (HTR), which occur within minutes or hours of the start of transfusion, include:

• Sudden onset of fever
• Shivering
• Lower back pain
• A sense of impending doom
• Shortness of breath
• Blood in urine
• Shock

These symptoms arise from errors in blood typing, patient identification, or compatibility testing. The transfusion should be stopped immediately and intravenous fluids administered to maintain normal intravascular volume. Diuretics may help preserve kidney function. Additional measures may be required in cases of disseminated intravascular coagulation, such as:

• Use of heparin
• Verification of patient and donor identification
• Rechecking the blood unit and notifying the blood bank that an alloantibody may have gone undetected⁴

Alloimmunisation

Patients with thalassaemia who receive multiple transfusions are known to develop alloimmunisation, which is the formation of alloantibodies against foreign red blood cells (RBCs).⁸

Transfusion-Transmitted Infections

Blood transfusion is a significant route of transmission for infectious organisms such as viruses, bacteria, and parasites. This risk should be mitigated through appropriate donor screening and blood donation selection processes.⁴

Iron Chelation Therapy: A Key Companion to Transfusions

Red blood cells contain haemoglobin, an iron-rich protein. Regular blood transfusions can lead to iron overload, which may result in life-threatening complications. Iron chelation therapy is used as a preventive measure to remove excess iron from the body in patients who receive frequent blood transfusions. Three medications are used for this purpose:

Deferasirox

Administered orally once daily. Side effects include:

• Skin rash
• Nausea
• Diarrhoea

Deferiprone

Considered an alternative when other options have failed. Side effects include:

• Reduction in white blood cell count
• Increased risk of infections

Deferoxamine

A liquid medication is administered slowly under the skin, typically via a small portable pump overnight. This treatment may take some time to be effective and can cause mild discomfort. Side effects include:

• Vision impairment
• Hearing impairment⁵

Summary

Thalassaemia is an inherited blood condition that causes lifelong anaemia because the body is unable to produce enough healthy haemoglobin. The severity of alpha thalassaemia, in which some or all alpha-globin genes are absent, can range from mild to life-threatening. Beta thalassaemia is caused by mutations in the beta-globin gene, resulting in three forms: minor (mild), intermedia (moderate), and major (severe). Patients with thalassaemia major often require frequent blood transfusions every few weeks to maintain haemoglobin levels, support healthy development, and prevent bone malformations. Individuals with thalassaemia intermedia may only need transfusions during periods of physiological stress such as illness, pregnancy, or surgery. Although transfusions significantly improve energy, oxygen levels, and overall quality of life, they also carry risks such as fever, infections, haemolytic reactions, allergic reactions, and iron overload. The most prevalent complication is iron overload, which is managed with iron-chelating medications such as deferasirox, deferiprone, or deferoxamine. In general, transfusion therapy helps patients live healthier lives by treating severe anaemia, while iron chelation therapy protects the organs from excess iron accumulation.